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Iranian Journal of Pharmaceutical Research (20 14), 13 (supplement): 125-132 
Received: April 2013 
Accepted: September 2013 



Copyright © 2014 by School of Pharmacy 
Shaheed Beheshti University of Medical Sciences and Health Services 



Original Article 

The Effect of Paxilline on Early Alterations of Electrophysiological 
Properties of Dentate Gyrus Granule Cells in Pilocarpine-Treated Rats 

Nasrin MehranfarcH, Hamid Gholamipour-Badie 6 c , Fereshteh Motamedi 6 , Mahyar JanahmadP >c 

and Nima Naderi a * 6 * 

a Department of Pharmacology and Toxicology, School of Pharmacy, Shahid Beheshti 
University of Medical Sciences, Tehran, Iran. h ^N euro science Research Center, Shahid Beheshti 
University of Medical Sciences, Tehran, Iran, department of Physiology, Faculty of Medicine, 
Shahid Beheshti University of Medical Sciences, Tehran, Iran. 



Abstract 

The dentate gyrus of hippocampus has long been considered as a focal point for studies 
on mechanisms responsible for the development of temporal lobe epilepsy (TLE). Change in 
intrinsic properties of dentate gyrus granule cells (GCs) has been considered as an important 
factor responsible in temporal lobe seizures. In this study we evaluated the intrinsic properties 
of GCs, during acute phase of seizure (24 h after i.p. injection of pilocarpine) compared to sham 
group using whole cell patch-clamp recordings. Our results showed a significant increase in the 
number of action potentials (APs) after applying depolarizing currents of 200 pA (p < 0.01) 
and 250pA (p < 0.05) compared to sham group. The evaluation of AP properties revealed a 
decrease in half-width of AP in GCs of seizure group (1.27 ± 0.03 ms) compared to sham group 
(1.60 ± 0.11). Moreover, addition of BAPTA to pipette solution prevented changes in AP half- 
width in seizure group (1.71 ± 0.11 ms) compared to sham group (1.91 ± 0.08 ms). In contrast, 
an increase in the amplitude of fast afterhyperpolarization was observed in GCs of seizure 
group (-11.68 ± 0.72 mV) compared to sham group (-8.28 ± 0.59 mV). Also, GCs of seizure 
group showed a significant increase in both firing rate and instantaneous firing frequency at 
depolarizing currents of 200 pA (P < 0.01) and 250 pA (P < 0.05) compared to sham group. 
The changes in electrophysiological properties of GCs were attenuated after bath application 
of paxilline suggesting possible involvement of large conductance Ca 2+ - activated K + channel 
(BK channel). Our results suggested the possible involvement of certain potassium channels 
in early changes of intrinsic properties of GCs which eventually facilitate TLE development. 

Keywords: Paxilline; Dentate gyrus; Granule cells; Epilepsy. 



Introduction 

Temporal lobe epilepsy (TLE) is the most 
common form of acquired epilepsy in adult and 
is often resistant to antiepileptic drug-therapy 
(1). In animal models, TLE is a situation that 



Corresponding author: 

E-mail: naderi.nima@gmail.com 



is induced after injection of pilocarpine (2), 
kainic acid (3), or electrical stimulation of a 
specific site of brain (4,5) and is associated with 
recurrent spontaneous seizures. Pilocarpine is a 
potent Ml muscarinic agonist and its systemic 
injection to rodents induces behavioral and 
electrophysiological changes in three distinct 
phases including acute phase which is caused 
by an initial brain insult and lasts 24 h, a latent 



MehranfardN etal. I IJPR (2014), 13 (supplement): 125-132 



phase that is a relatively seizure-free period and 
lasts between 4-44 days and a chronic phase in 
which spontaneous recurrent seizure occurs 

(6) . After a brain insult, a cascade of brain 
reorganization events termed epileptogenesis is 
induced which lead to changes in brain excitability 
and occurrence of spontaneous recurrent seizures 

(7) . Dentate gyrus granule cells (GCs) has long 
been recognized as a focal point for studies on 
mechanisms responsible for epileptogenesis. In 
recent years, much attention has been focused 
on changes in the intrinsic properties of neurons 
especially the role of K + channels as a possible 
mechanism in epileptogenesis and generation 
of hippocampal epilepsy. For instance, Brenner 
and coworkers in 2005 reported that p4 subunit 
of large conductance Ca 2+ activated K + channels 
(BK channels) reduces excitability of dentate 
gyrus GCs preventing temporal lobe seizures (8). 

Despite many studies on hippocampal 
seizure, there is little information regarding 
early events that initiate epileptogenesis in 
dentate gyrus. Identification of early alterations 
in electrophysiological properties of GCs would 
enable us to know how these changes might 
contribute to the epilepsy. In this study, we 
evaluated changes in the intrinsic properties of 
GCs during acute phase of pilocarpine-induced 
seizure using whole cell patch clamp recordings. 

Experimental 

Animals 

Male wistar rats weighting 150-200 g 
(Pasteur Institute, Tehran, Iran) were used in this 
study. The animals were housed in colony cages 
(5 rats per cage) with free access to food and tap 
water under standardized housing conditions 
with a 12 h light-dark cycle (lights on at 7:00 
a.m.) and temperature-controlled (22 ± 1 °C) 
environment. All procedures were in accordance 
with the National Institute of Health Guide for 
the Care and Use of Laboratory Animals (NIH 
Publications No. 80-23, revised 1996) and were 
approved by the local Research and Medical 
Ethics Committee. 

Drugs 

Rats were treated with pilocarpine (350 
mg/Kg, ip\ Sigma-Aldrich Co. St Louis, 



USA) 20 min after methyl scopolamine (5 
mg/Kg, S.C; Sigma-Aldrich Co. St Louis, USA) 
administration in order to reduce the peripheral 
effects of pilocarpine. Diazepam (4 mg/kg, 
ip; Sigma-Aldrich Co. St Louis, USA) was 
administered after 3 h to stop status epilepticus 
(SE). Only motor seizures of grade 3 or greater 
on the Racine scale (9) were scored. 

Patch-clamp recordings in hippocampal 
slices 

Slice preparation 

Twenty-four hours after seizure induction, 
rats were anaesthetized with ether and then 
decapitated. The brains were quickly removed 
and chilled in ice-cold slicing solution 
containing (in mM): 125 NaCl, 2.8 KC1, 1 
CaCl 2 , 1 MgCl 2 , 2 MgS0 4 , 1.25 NaH 2 P0 4 , 26 
NaHC0 3 , 10 D-glucose and set to pH of 7.4 
(with 95% oxygen and 5% carbon dioxide); 
the osmolarity was adjusted to 305 mOsm by 
addition of sucrose to the solution. The brain 
transverse slices containing hippocampal area 
were cut into 350-400 \im using a vibroslicer 
(752 M, Campden Instruments Ltd, UK). The 
slices were then incubated in ACSF containing 
(in mM): 124 NaCl, 2.8 KC1, 2 CaCl 2 , 2 MgS0 4 
,1.25 NaH 2 P0 4 , 26 NaHC0 3 , and 10 D-glucose 
at pH 7.4, the osmolarity of 295 mOsm and 
temperature of 32-35 °C for lh and stored at 
22-24 °C (room temperature) before being 
transferred to the recording chamber. 

Electrophysiology 

The slices were transferred to a submerged 
recording chamber and were continuously 
perfused with ACSF (1-2 mL/min) at room 
temperature. Dentate gyrus GCs were visualized 
by infrared videoimaging (Hmamatsu, ORSA, 
Japan) with a 40x water immersion objective. 
Recordings were made using glass electrodes 
pulled with a two-stage vertical puller (PC 10, 
Narishige, Japan) from borosilicate glass 
capillary (1.2 mm O.D., 0.95 mm I.D.). The 
pipettes had a resistance of 3-6 MQ and filled 
with intracellular solution containing (in mM) 
135 potassium methylsulfate (KMeS0 4 ), 10 
KC1, 10 HEPES, 1 MgCl 2 , 2 Na 2 ATP, and 0.4 
Na 2 GTP. The pH of internal solution was adjusted 
to 7.3 by KOH, and the osmolarity was set to 



126 



The Effect of Paxilline on Early Alterations of Electrophysiological 



295 mOsm. Whole-cell patch-clamp recordings 
were made from dentate gyrus GCs using 
Multiclamp 700B amplifier (Axon Instruments, 
Foster City, CA) equipped with Digidata 1320 
A/D converter (Axon Instruments, Foster City, 
CA). Recordings were only obtained when seals 
of more than 1GQ resistance were established. 
The function of test seal was frequently checked 
during the experiment to ensure that the seal is 
stable. Access resistance was less than 20 MQ 
and less than 20% change during recordings 
was acceptable in order to include the recording 
for further analysis. In addition, only cells 
with resting membrane potential (RMP) more 
hyperpolarized than -70 mV, input resistance 
(R. n ) >200 MQ, and obvious overshoot of action 
potential (AP) were included in analysis. In 
certain recordings, paxilline (1 |LiM; Sigma- 
Aldrich Co. St Louis, USA) was included in 
bath solution (10), and 1,2-Bis (2-amino-5- 
bromophenoxy) ethane-A^A^TV'-tetraacetic 
acid (BAPTA; 10 mM) was applied in the pipette 
solution . Electrophysiological recordings 
were sampled at 10 kHz, filtered at 5 kHz 
and stored for offline analysis. To investigate 
the electrophysiological properties of GCs in 
current clamp mode, trains of APs were elicited 
by applying depolarizing currents (50-250pA; 
1000 ms) while the cell was hold at -75 mV. AP 
characteristics were measured based on the first 
AP elicited by the depolarizing current of 200pA 
(11). Passive and active electrophysiological 
parameters including RMP, R n , the number 
of APs, fast after-hyperpolarization (fAHP) 
amplitude, AP duration at half-width, decay 
time, instantaneous firing frequency (IFF) were 
measured. R n was defined by the steepest slope of 
the I-V curve based on steady-state responses to 
hyperpolarizing current pulses (50-200 pA, 300 
ms). The AHP amplitude was measured from the 
level of RMP to the peak of the hyperpolarization. 
AP half- width was measured before and 15 min 
after bath application of paxilline to ensure 
that maximum effects were obtained. IFF was 
measured as 1 /interval between the first and the 
second AP. 

Statistical analysis 

Data were shown as mean ± S.E.M. The 
Student) s unpaired t-test, one-way ANOVA and 



two-way ANOVA followed by Bonferroni's 
post-test were used as appropriated. A p-value 
less than 0.05 were considered statistically 
significant. 

Results 

The passive membrane properties of GCs, 
such as RMP and R in did not affect by pilocarpine - 
induced seizure nor by Paxilline application 
(data not shown). 

Paxilline reversed hyperexcitability of 
dentate gyrus GCs in acute phase of pilocarpine- 
induced seizure 

The excitability of GCs during acute phase 
of seizure was evaluated by measuring the 
number of APs elicited by depolarizing current 
pulses ranging from 50 to 250 pA. Figure 1A 
showed traces of APs. Injection of depolarizing 
currents into granule cells significantly increased 
the number of action potentials in acute seizure 
group compared to sham group [F (1 , 72) = 23 .06, 
p < 0.0001; Figure IB]. Further analysis using 
Bonferroni's post-test revealed a significant 
increase in number of APs at 200 (p < 0.01) and 
250 pA (p < 0.05) compared to sham group. Bath 
application of paxilline significantly attenuated 
seizure-induced increase in APs at 200pA (p < 
0.05) and 250 pA (p < 0.01) compared to seizure 
group. 

Changes in fAHP and AP half-width during 
acute phase of pilocarpine-induced seizure were 
reversed by paxilline 

In order to further illustrate the mechanisms 
involved in regulation of GCs firing rate, fAHP 
and half-width of the first AP were measured 
after injection of the depolarizing current pulse 
of 200pA. Figure 2A shows a representative 
trace of the firs AP in sham, acute seizure, and 
seizure -paxilline group. As shown in Figure 
2B, the fAHP of the first AP was significantly 
changed in different groups [F (3, 25) = 4.48; p 
= 0.012]. Further analysis revealed a significant 
increase (p < 0.01) in fAHP of cells in seizure 
group (-11.67 ± 0.72 mV; N = 8) compared to 
sham group (-8.28 ± 0.59 mV; N = 8). Bath 
application of paxilline, significantly reversed 
seizure-induced increase in fAHP amplitude 



127 



MehranfardN etal. I IJPR (2014), 13 (supplement): 125-132 



Sham 



Acute seizure 



Acule-paxiHline 



£uuren[ injection 



B 



II II I 



JIIIBil^ JlillL^- 



_JLiiiL _|liiiLiiii ^JteJiL 

^llli-L _JlllllliiU|^ _ Jiiii\__ Jfum^ 

J — L J L J L _ 



SOpA. 



lOQpA 



ISDpA 



2S0pA 



30n 



+3 
C 

I 

O 20 
Q. 

C 

o 

2 10- 

0) 

E 

3 



Sham 

Sham-Paxilline 
Acute Seizure 
Acute Seizure-Paxilline 



JL 



100 



150 200 

Current injection(pA) 



250 



Figure 1. Alteration in the firing rate of dentate gyrus GCs recorded 24 h after pilocarpine-induced seizure. (A) Representative traces 

show the differences in firing rate of the GCs in response to 1000 ms depolarizing pulses from 50 pA to 250 pA in sham (above), acute 

seizure (middle) and acute seizure + paxilline (down) groups. (B) Depolarizing current injection ranging from 50 pA to 250 pA increased 

the number of APs in seizure group compared to sham group. The application of paxilline (1 uM) reversed pilocarpine-induced increase 

in APs. Data were shown as mean+SEM (N = 10). 

*p<0.05, **p<0.01 significant difference compared to sham group. 

+p < 0.05, ++p<0.01 significant difference compared to acute seizure group. 



(p < 0.01) toward sham group (-9.26 ± 0.42 
mV, N = 8). Moreover, as shown in Figure 2C, 
a significant change was observed in the half- 
width of AP in different groups [F (3, 23) = 
6.605; p = 0.002]. Further analysis revealed a 
significant decrease (p < 0.01) in the half- width 
of the first AP in seizure group (1.27 ± 0.03 ms; N 
= 7) compared to sham group (1.60 ±0.11 ms; N 
= 8). Decrease in AP half- width of seizure group 
could be due to decrease in decay time of AP 
(Figure 2D), suggesting the role of K + channels 



in reduction of half-width. Bath application 
of paxilline, significantly reversed (p < 0.01) 
seizure-induced changes in the half-width of AP 
toward sham group (1.69 ± 0.08 ms; N = 8). 

Application of BAPTA increased half width 
to normal values 

The Ca 2+ -activated K + channels are activated 
by both membrane depolarization and increase 
in intracellular Ca 2+ concentration [Ca 2+ ]. 
(12,13). In order to examine the role of [Ca 2+ ] 



128 



The Effect 



of Paxilline on Early Alterations of Electrophysiological 




Figure 2. Pilocarpine-induced changes in AHP amplitude and AP half-width were reversed by bath application of paxilline. 
(A) Representative trace of 1st AP of sham, acute seizure and acute seizure + paxilline groups during a train of AP evoked by 200 pA 
current injection for 1000 ms. (B) fAHP amplitude was measured from the level of RMP to the peak of the hyperpolarization. fAHP 
amplitude significantly increased during acute phase of pilocarpine-induced seizure compared to sham group. Paxilline decreased fAHP 
amplitude to the sham values. (C) AP half- width significantly decreased during acute phase of seizure. Paxilline increased AP half- width 
to normal values and reversed the effect of seizure on AP half- width. (D) The decay time of AP was increased in pilocarpine-induced 
seizure group and was reversed after bath application of paxilline. 
*p<0.05, **p<0.01 significant difference compared to sham group. 
++p<0.01, +++p<0.001 significant difference compared to acute seizure group. 
##p<0.01 significant difference compared to sham + paxilline group. 



. in firing rate of GCs, the Ca 2+ chelator BAPTA 
(10 mM) was added to the internal solution from 
both sham and acute seizure group. Application 
of BAPTA prevented change in AP half- width in 
seizure group (1.71 ±0.11 ms; N = 5) compared 
to that of BAPTA-sham cells (1.91 ± 0.08 ms; 
N = 5), suggesting a role of intracellular Ca 2+ in 
firing frequency (Figure 3). 



Increase in IFF after seizure is reversed by 
paxilline application 

As shown in Figure 4, IFF was significantly 
enhanced after seizure [F (2, 39) = 15.94, P < 
0.0001]. Further analysis using Bonferroni's 
post-test revealed a significant increase in IFF 
at 200 pA (P < 0.01) and 250 pA (P < 0.05) 



129 



MehranfardN etal. I IJPR (2014), 13 (supplement): 125-132 




Figure 3. Effect of BAPTA on AP half-width. Application of 
BAPTA prevented change in AP half-width in seizure group 
compared to that of BAPTA-sham cells. Data were shown as 
mean + SEM (N = 5). 



compared to sham group. Bath application of 
paxilline significantly reduced IFF to sham 
values at 150 pA (P < 0.05), at 200 pA (P < 0.01), 
and 250 pA (P < 0.05), compared to those of 
sham group, suggesting the possible role of BK 
channel in enhancement of the firing rate. 

Discussion 

There are several documents that show 
the role of dentate gyrus in epileptogenesis 
(14). Although seizure-induced changes in 
hippocampal neurons have been studied 
extensively, the mechanisms that initiate 
epileptogenesis have not been fully established. 
In this study, we focused on intrinsic 
membrane properties of granule cells 24 h 
after seizure induction and demonstrated that 
pilocarpine-induced seizures altered intrinsic 
membrane properties of the dentate gyrus GCs. 
Pilocarpine caused a significant increase in the 
firing frequency, the fAHP amplitude, and the 
IFF while caused a significant reduction in AP 
half- width and decay time in GCs during acute 
phase of seizure. Previous studies reported 
that pilocarpine-induced seizure induces 
hyperexcitability of hippocampal cells during 
early stages of epileptogenesis. Using field 



potential recording, a hyperexcitability, as 
a transient increase of the input and output 
field responses, has been shown during the 
latent period of epileptic animals which may 
participate in development of epilepsy (15). In 
other study, patch-clamp recording from GCs 
in dentate gyrus revealed that the stimulation 
of perforant pathway produce hyperexcitability 
of GCs as an increase in the number of action 
potentials (16). In our study, for the first 
time, a significant change in certain intrinsic 
properties of GCs was reported which could 
result in hyperexcitability of these cells. Also, 
our results showed that bath application of 
paxilline attenuated the increase in firing rate 
of GCs to normal values and reversed the 
effects of pilocarpine on fAHP amplitude, AP 
half-width, decay time and IFF, suggesting the 
role of K + channels, including BK channels, in 
hyperexcitability of GCs during acute phase of 
TLE. The BK channels are widely expressed 
in CNS and are gated both by voltage and by 
intracellular Ca 2+ ions. These channels not only 
contribute to action potential repolarization 
and shape the fAHP (17,18), but can also affect 
neuronal firing patterns (19,20). A relation 
between seizure and gain-of-function of BK 
channel has been associated with high firing 
rate of neocortical neurons with an increase 
in the AHP amplitude and a decrease in AP 
half- width (21). Moreover, a gain- of-function 
of BK channel activity in genetic epilepsy 
both in human and mice have been associated 
with recurrent seizures (22,8). The changes 
in neuronal excitability has been shown in 
other conditions related to synaptic plasticity, 
such as learning, where it could be modulated 
by changing the amplitude of AHP (23). 
BK channels are one of the most prominent 
ion channels which have been shown to be 
involved in the generation of the fAHP (24). 
The mechanism by which BK channel activity 
increases the firing rate might contribute to a 
faster repolarization and a more deinactivation 
of Na + channels that occurs during the fAHP, 
increasing Na + channel availability and this 
resulted in firing with short latencies (19). The 
observed changes in the intrinsic properties 
of GCs is likely attributed to [Ca 2+ ]i, as the 
elimination of intracellular Ca 2+ using BAPTA 



130 



The Effect of Paxilline on Early Alterations of Electrophysiological 



80- 
60- 

x 

40- 

LL 

20- 



Sham 

Acute Seizure 

Acute Seizure-Paxilline 




150 200 250 

Current injection (pA) 



Figure 4. Seizure-induced increase in instantaneous firing 
frequency (IFF) was reversed by paxilline application. IFF was 
measured as the reciprocal of interval between the first and the 
second AP during 200 pA current injection. IFF significantly 
increased during acute phase of pilocarpine-induced seizure. 
After bath application of paxilline, IFF returned to sham levels. 
Data were shown as mean ± SEM (N = 6 in each group). 
*p<0.05, **p<0.01 significant difference compared to sham 
group. 

+p<0.05, ++p<0.01 significant difference compared to acute 
seizure group. 



reversed the decreased half-width of APs 
during acute phase of TLE. Consistent with our 
results, recent studies have shown an increase 
of [Ca 2+ ]i in rat hippocampal CA1 neurons 
during the acute phase of pilocarpine model 
of seizure (25,26) which could induce gain-of- 
function of BK channels. 

In conclusion, these results suggest that 
pilocarpine-induced hyperexcitability in dentate 
gyrus GCs during acute phase could result from 
alterations in the intrinsic properties of the cells, 
particularly those related to potassium channels 
activation which could give rise to an increase in 
the firing rate of GCs. Considering the possible 
role of BK channel activity in early stages of 
epileptogenesis, the blockade of these channels 
might have a potential therapeutic effect in 
prevention of synaptic plasticity required for 
recurrent seizure occurrence. 

Acknowledgment 

This work is part of Ph.D. dissertation of N. 
Mehranfard at Shahid Beheshti University of 
Medical Sciences. 



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